Novel 2-aminomethyl-4-,6-dihalogenphenol derivatives and methods for the preparation thereof

Abstract

2-AMINOMETHYL-4,6-DIHALOGENPHENOL DERIVATIVES AND SALTS THEREOF WITH PHYSIOLOGICALLY ACCEPTABLE ACIDS OR BASES HAVING THE FORMULA: ##STR1## wherein X is the same halogen in both positions, R 1 is a hydrogen atom or a lower alkyl group, R 2 is an alkyl, cycloalkyl, aryl or aralkyl group, or R 1 and R 2 together with the nitrogen atom may form a saturated heterocyclic ring, which ring may be interrupted by an oxygen, nitrogen or sulfur atom, R 3 is a hydrogen atom, an alkyl, alkoxyalkyl, carboxyalkyl, carbamylalkyl, aralkyl, acyl or sulfonyl group or a base radical, e.g. an alkali metal atom, and R 3 " is a cyanoalkyl, hydroxyalkyl, carbalkoxy-alkyl, N,N-dialkylcarbamyl, N-alkylcarbamyl-alkyl or N,N-dialkylcarbamylalkyl group, are useful as diuretics and saluretics; some derivatives possess secretolytic activity.

Having thus described my invention, what I desire to secure by Letters Patent and hereby claim is: 
     
       1. A compound of the formula: ##STR23## wherein X is the same halogen in both positions, R 1  is a hydrogen atom or a lower alkyl group, R 2  is an alkyl, cycloalkyl, aryl or aralkyl group, or R 1  and R 2  together with the nitrogen atom may form a saturated heterocyclic ring, which ring may be interrupted by an oxygen, nitrogen or sulfur atom, and R 3  is carboxylalkyl, carbamylalkyl, acyl, carbalkoxyalkyl, N,N-dialkylcarbamyl, N-alkylcarbamyl-alkyl or N,N-dialkylcarbamylalkyl group and salts thereof with physiologically acceptable acids or bases. 
     
     
       2. A compound as claimed in claim 1 wherein X is bromine, R 1  is methyl, R 2  is cyclohexyl and R 3  is CH 2  CO.N(CH 3 ) 2 . 
     
     
       3. A compound as claimed in claim 1 wherein X is bromine, R 1  is methyl, R 2  is cyclohexyl and R 3  is CH 2  CO.N(C 2  H 5 ) 2 . 
     
     
       4. A compound as claimed in claim 1 wherein X is chlorine, R 1  is methyl, R 2  is cyclohexyl and R 3  is CH 2  CO.N(C 2  H 5 ) 2 . 
     
     
       5. A compound as claimed in claim 1 wherein X is bromine, R 1  is CH 3 , R 2  is cyclohexyl and R 3  is CH 2  COOC 2  H 5 . 
     
     
       6. A method of preparing compounds of the formula: ##STR24## wherein X is the same halogen in both positions, R 1  is a hydrogen atom or a lower alkyl group, R 2  is an alkyl, cycloalkyl, aryl or aralkyl group, or R 1  and R 2  together with the nitrogen atom may form a saturated heterocyclic ring, which ring may be interrupted by an oxygen, nitrogen or sulfur atom, and R 3  is carboxyalkyl, carbamylalkyl, acyl, carbalkoxyalkyl, N,N-dialkylcarbamyl, N-alkylcarbamyl-alkyl or N,N-dialkylcarbamylalkyl group and salts thereof with physiologically acceptable acids or bases, said method comprising reacting a 2,4-dihalogenphenol of the formula: ##STR25## wherein X is as defined above with formaldehyde and an amine of the formula: ##STR26## wherein R 1  and R 2  are as defined above to obtain a 2-amino-methyl-4,6-dihalogen-phenol of the formula: ##STR27## and synthesizing the corresponding O-substituted derivatives of the formula (I) by further reacting the free phenolic component (IV) or its alkali phenolate with a compound of the formula:   Y -- R.sub.3 '                                             (V)     wherein R 3  ' has the same meaning as R 3  and Y is a reactive group splittable from said R 3  ' during said reaction with said compound of the formula (IV).   
     
     
       7. The method of claim 1 of preparing compounds of the formula: ##STR28## wherein X, R 1  and R 2  are as defined in claim 6 and R 3  " is a carbalkoxyalkyl, N,N-dialkylcarbamyl, N-alkylcarbamyl-alkyl or N,N-dialkylcarbamylalkyl group. 
     
     
       8. The method of claim 7, wherein the reaction between the compound of the formula (IV) and the compound of the formula (V) is carried out in an aprotic solvent or an inert solvent mixture containing at least one aprotic solvent. 
     
     
       9. The method of claim 8, wherein the reaction is carried out in the presence of a basic condensing agent. 
     
     
       10. The process of claim 6 wherein said reaction between the compound of the formula (II) with formaldehyde and the amine of the formula (III) is carried out in an inert solvent. 
     
     
       11. The process of claim 6 wherein Y is a halogen atom. 
     
     
       12. The process of claim 6 wherein said compound of the formula (I) is converted to a physiologically acceptable salt thereof with a physiologically acceptable acid or base. 
     
     
       13. The process of claim 12 wherein R 3  is a carbalkoxyalkyl, N,N-dialkylcarbamyl, N-alkylcarbamyl-alkyl or N,N-dialkylcarbamylalkyl group. 
     
     
       14. The method of claim 9, wherein the basic condensing agent is selected from the group consisting of sodium methylate, triethylamine and sodium hydride. 
     
     
       15. The method of claim 7, wherein the reaction between the compound of the formula (IV) and the compound of the formula (V) is carried out in the presence of a basic condensing agent. 
     
     
       16. The process of claim 15, wherein the basic condensing agent is selected from the group consisting of sodium methylate, triethylamine and sodium hydride.